Human programmed death 1 receptor (hPD-1) is an important class of immune negative regulatory molecules (also known as “immune checkpoint molecules”), which belongs to CD28 family, members of which also include CD28, CTLA4, ICOS and BTLA, and the like.
PD-1 is a type I transmembrane glycoprotein composed of three regions: an extracellular region, a transmembrane region and an intracellular region. Its extracellular membrane region is an immunoglobulin variable region (IgV)-like domain. The N-terminal of its intracellular region contains an immunoreceptor tyrosine based inhibitory motif (ITIM), and the C-terminal contains an immunoreceptor tyrosine based switch motif (ITSM), in which ITSM is the key motif for PD-1 molecules to transmit inhibitory signals into the cell. Unlike CTLA-4 and other family members, which present in the form of homodimers on the surface of T cells, PD-1 is expressed as a monomer on the surface of activated T cells, B cells, and myeloid cells and the like.
PD-1 has two ligands, i.e., PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), which belong to transmembrane molecules of B7 family. PD-L1 widely distributes on the surface of hematopoietic cells such as mature macrophages, B cells, dendritic cells, as well as non-hematopoietic cells such as endothelial cells, islet cells, and mast cells, and is highly expressed on the surface of various tumor cells; PD-L2 is only expressed on the surface of some cells such as macrophages, dendritic cells, and some B cell subtypes. Similar to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a classical immune negative regulatory molecule, PD-1 exerts immune negative regulation through its interaction with its ligands PDL1 and PDL2. When PD-1 interacts with its ligands, its intracellular segment ITSM is phosphorylated and recruits corresponding phosphorylating enzymes SHP-1 and SHP-2, resulting in dephosphorylation of downstream signaling molecules, thereby downregulating the immune cell response level. This negative regulatory mechanism of the immune system is a key molecular basis for maintaining immune tolerance of the body. However, a number of studies have shown that the overexpression of the immune negative regulatory molecules such as PD-1 and the immunosuppressive state of the body induced by its interaction with receptor PD-L1/PD-L2 plays an important role in the pathogenetic processes of cancers and chronic infectious diseases such as HIV, HCV, and HBV, and the like. By blocking the interaction between PD-1/PD-L1, the immunosuppression can be reversed, and the ability of the immune system to kill viruses and tumor cells may be enhanced; the effect of reversing the immunosuppressive state is better if PD-1/PD-L2 interaction is blocked simultaneously. Therefore, the targeting to such negative regulatory molecules has become a new cancer treatment strategy, and studies on PD1/PDL1 pathway inhibitors have attracted much attention. Antibody drugs that specifically block the PD1/PDL1 signaling pathway are the focus of the research in this area. PD1 antibodies Nivolumab (Opdivo, Bristol-Myers Squibb) and Pembrolizumab (Keytruda, Merck) both received FDA breakthrough therapy designations and were approved for marketing. Among them, Nivolumab of Bristol-Myers Squibb was approved by the FDA for marketing in December 2014, for clinical treatment of melanoma; then in March 2015, this antibody was approved by FDA for the treatment of squamous non-small cell lung cancer, indicating that such immunotherapies officially entered the field of clinical treatment of solid tumors.
There remains a need in the field for antibody drugs that specifically block the PD1/PDL1 signaling pathway.